PURPOSE: Diabetic nephropathy (DN) is one of the most common diabetic microvascular complications. Inflammatory factors participate in each stage of DN, and nuclear factor (NF)-κB and monocyte chemoattractant protein-1(MCP-1) play important mediation roles. The purpose of this study was to investigate the renal protective effects of a diet and exercise intervention in a rat model of Type 2 diabetes mellitus (T2DM). METHOD: Control rats (Group A, n = 10) were fed a normal diet, while 30 rats were fed a high-glucose, high-fat diet and given an intraperitoneal injection of streptozocin to establish the T2DM model. Model rats (n = 8 per group) were randomized into Groups B, C, and D. Groups C and D were treated with glibenclamide, and Group D received an 8-week diet and exercise intervention. Blood, 12-hr urine, and kidney tissue samples were collected postintervention for detecting blood glucose and lipid levels, expression of MCP-1 and NF-κB, and renal function indices. RESULTS: Postintervention, blood glucose, and lipid levels in Groups C and D were lower than those in Group B, with decreases in Group D significantly greater than in Group C. Every index of renal protection showed greater improvement in Group D than in Group C (p < .05). The expression of NF-κB and MCP-1 was lower in Group D than in Group C (p < .05). CONCLUSIONS: The diet and exercise intervention reduced the inflammatory reaction and delayed T2DM and DN progression by inhibiting the activation of NF-κB and downregulating the expression of MCP-1.